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Safety and Efficacy of Oxaliplatin and Fluoropyrimidine Regimens With or Without Bevacizumab As First-Line Treatment of Metastatic Colorectal Cancer: Results of the TREE Study

Howard S. Hochster, Lowell L. Hart, Ramesh K. Ramanathan, Barrett H. Childs, John D. Hainsworth, Allen L. Cohn, Lucas Wong, Louis Fehrenbacher, Yousif Abubakr, M. Wasif Saif, Lee Schwartzberg, Eric Hedrick

From the New York University Cancer Institute, New York, NY; Florida Cancer Specialists, Fort Myers, FL; University of Pittsburgh Cancer Institute, Pittsburgh, PA; sanofi-aventis, Bridgewater, NJ; Sarah Cannon Cancer Center, Nashville; West Cancer Clinic, Memphis, TN; Rocky Mountain Cancer Center, Denver, CO; Scott & White Hospital, Center for Cancer Prevention and Care, Temple, TX; Department of Oncology/Hematology, Kaiser Permanente, Vallejo Medical Center, Vallejo, CA; Florida Oncology Association, Jacksonville, FL; Yale University School of Medicine, New Haven, CT; and Genentech BioOncology, South San Francisco, CA

Corresponding author: Howard S. Hochster, MD, New York University Cancer Institute, 160 East 34th St, New York, NY 10016; e-mail: Howard.Hochster{at}med.nyu.edu

Purpose: To evaluate the safety and efficacy of three oxaliplatin and fluoropyrimidine regimens, with or without bevacizumab, as first-line treatment for metastatic colorectal cancer (CRC).

Patients and Methods: Patients with histologically documented metastatic or recurrent CRC and no prior treatment for advanced disease were randomly assigned to mFOLFOX6 (bolus and infusion fluorouracil [FU] and leucovorin [LV] with oxaliplatin), bFOL (bolus FU and low-dose LV with oxaliplatin), or CapeOx (capecitabine with oxaliplatin), respectively (Three Regimens of Eloxatin Evaluation [TREE-1]). The study was later modified such that subsequent patients were randomized to the same regimens plus bevacizumab (TREE-2).

Results: A total of 150 and 223 patients were randomly assigned in the TREE-1 and TREE-2 cohorts, respectively. Incidence of grade 3/4 treatment-related adverse events during the first 12 weeks of treatment were 59%, 36%, and 67% for mFOLFOX6, bFOL, and CapeOx, respectively, (TREE-1) and 59%, 51%, and 56% for the corresponding treatments plus bevacizumab (TREE-2; primary end point). CapeOx toxicity in TREE-1 included grade 3/4 diarrhea (31%) and dehydration (27%); capecitabine dose reduction to 1,700 mg/m²/d in TREE-2 resulted in improved tolerance. Overall response rates were 41%, 20%, and 27% (TREE-1) and 52%, 39%, and 46% (TREE-2); median overall survival (OS) was 19.2, 17.9, and 17.2 months (TREE-1) and 26.1, 20.4, and 24.6 months (TREE-2). For all treated patients, median OS was 18.2 months (95% CI, 14.5 to 21.6; TREE-1) and 23.7 months (95% CI, 21.3 to 26.8; TREE-2).

Conclusion: The addition of bevacizumab to oxaliplatin and fluoropyrimidine regimens is well tolerated as first-line treatment of mCRC and does not markedly change overall toxicity. CapeOx tolerability and efficacy is improved with reduced-dose capecitabine. First-line oxaliplatin and fluoropyrimidine-based therapy plus bevacizumab resulted in a median OS of approximately 2 years.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.